Tumor microenvironment‐responsive delivery nanosystems reverse immunosuppression for enhanced CO gas/immunotherapy

Abstract Carbon monoxide (CO) gas therapy demonstrates great potential to induce cancer cell apoptosis and antitumor immune responses, which exhibits tremendous potential in cancer treatment. However, the therapeutic efficacy of CO therapy is inhibited by the immunosuppressive tumor microenvironment (TME). Herein, a facile strategy is proposed to construct hollow‐structured rough nanoplatforms to boost antitumor immunity and simultaneously reverse immunosuppression by exploring intrinsic immunomodulatory properties and morphological optimization of nanomaterials. The TME‐responsive delivery nanosystems (M‐RMH) are developed by encapsulating the CO prodrug within hollow rough MnO 2 nanoparticles and the subsequent surface functionalization with hyaluronic acid (HA). Rough surfaces are designed to facilitate the intrinsic properties of HA‐functionalized MnO 2 nanoparticles (RMH) to induce dendritic cell maturation and M1 macrophage polarization by STING pathway activation and hypoxia alleviation through enhanced cellular uptake. After TME‐responsive degradation of RMH, controlled release of CO is triggered at the tumor site for CO therapy to activate antitumor immunity. More importantly, RMH could modulate immunosuppressive TME by hypoxia alleviation. After the combination with aPD‐L1‐mediated checkpoint blockade therapy, robust antitumor immune responses are found to inhibit both primary and distant tumors. This work provides a facile strategy to construct superior delivery nanosystems for enhanced CO/immunotherapy through efficient activation of antitumor immune responses and reversal of immunosuppression.